Delivery of drugs by the transdermal route has been known to be theoretically possible for many years. The earliest developed transdermal patches were medicated bandages, usually with the drug mixed into the adhesive, designed to bring a known quantity of drug to a known area of skin for a known time. Such devices do not control the rate at which the drug is released. Controlled release transdermal patches rely for their effect on delivery of a known flux of drug to the skin for a prolonged period of time, measured in hours, days or weeks. Two mechanisms are used to control the drug flux from the patch: either the drug is contained within a drug reservoir, separated from the skin of the wearer by a synthetic membrane, through which the drug diffuses; or the drug is held dissolved or suspended in a polymer matrix, through which the drug diffuses to the skin. Patches incorporating a reservoir and membrane will deliver a steady drug flux across the membrane as long as excess undissolved drug remains in the reservoir; matrix or monolithic devices are typically characterized by a falling drug flux with time, as the matrix layers closer to the skin are depleted of drug. To date limited commercial exploitation of the transdermal administration route has been achieved, because of the many practical problems to be overcome with real systems. The skin is an effective barrier against the majority of drugs. Unless the delivery device is made unacceptably large, or the natural skin permeation rate of the drug is increased, then the drug flux across the skin is inadequate for useful therapy. Thus although in theory any drug might be delivered by this route, serious investigation of candidate drugs has been limited to a few where there are strong indications for transdermal use, namely: small molecular size; short half-life; rapid metabolization by the liver, rapid degradation in the GI tract; other problems with oral administration; high in vivo skin permeability; and high potency, i.e. small effective therapeutic dose. Despite active work in the field since at least 1970, at present commercial patches are available for delivery of only four drugs: nitroglycerin, scopolamine, clonidine, and estradiol.
The U.S. Surgeon General has determined that cigarette smoking is a major risk factor in coronary heart disease and is the cause of approximately 30% of all cancer deaths. However, it is very difficult to give up smoking, and any smoking cessation therapy has to deal with both the pharmacological and the psychological dependence on cigarettes. Separating the treatment of these two factors is an approach that has been tried with modest success, for example by satisfying the pharmacological craving with nicotine pills or chewing gum, while treating the psychological addiction independently. To date, the best results have been obtained with nicotine chewing gum, which achieves direct delivery to the systemic circulation by buccal absorption. However, chewing gum formulations taste bad, may lead to mouth ulcers and heartburn, cannot be used effectively by denture wearers, and depend entirely on the patient following the prescribed chewing regime. Other difficulties associated with oral administration include stomach upsets, nausea, rapid nicotine degradation, and irregular and unpredictable blood plasma levels.
Nicotine is very volatile, highly lipid soluble, and is known to permeate the skin easily, as happens for instance in the case of green tobacco sickness. The concept of applying the teachings of transdermal drug therapy to the delivery of nicotine has been recognized, and various research programs in the area, exemplified by the references below, have been undertaken.
German Patent Disclosure DE No. 3438284 discusses the general idea of delivering nicotine transdermally, and mentions that nitroglycerin is now available by the transdermal route.
Japanese Laid Open Application No. 61-251619 describes transdermal nicotine delivery using adhesive tapes in which 2-10% nicotine is mixed with the adhesive material. Nicotine delivery is controlled by the skin permeability. The tape is applied to the skin in strips about 70 cm.sup.2 in area.
U.S. Pat. No. 4,597,961 discloses a transdermal patch with a reservoir of nicotine and a microporous membrane to control the nicotine flux. Patches of this design can be effective for periods up to 45 minutes.
A paper by J. E. Rose et al., "Transdermal Administration of Nicotine", Drug and Alcohol Dependence, 13, 209-213 (1984) discusses the physiological effects observed as a result of directly applying an aqueous solution containing 9 mg of nicotine to the skin, and covering the treated area with occlusive tape. Noticeable effects were observed for two hours.
There are substantial problems to be overcome in developing a transdermal nicotine system. First, at room or body temperature, nicotine is a volatile, reactive liquid and a strong solvent. Many of the common materials from which components of patches, such as backings, adhesives, membranes, matrices and peel strips, are made, are dissolved, attacked or degraded by nicotine. For example, adhesives become stringy, lose their tackiness, or become so heavily loaded with nicotine that they deliver a huge burst of nicotine when applied to the skin. Typical grades of polyisobutylene, acrylate or silicone-based adhesives behave this way when exposed to nicotine for periods as little as one week. Polymers that swell significantly, disintegrate, or dissolve completely in the presence of liquid nicotine include many grades of polyvinyl chloride, polycarbonate, polystyrene, polyethylene terephthalate, polybutyrate, polyurethane, ethylene-vinyl acetate copolymers, except those with low percentages of vinyl acetate, and Saran (polyvinylidene chloride). Polymers that can withstand physical or chemical attack frequently exhibit high nicotine permeabilities, making retention of nicotine within the system a problem. For example, ethylene vinyl acetate with vinyl acetate content less than 10% is not visibly attacked or dissolved by nicotine. However, the nicotine permeability through a 100-150 .mu.m thick film of this material is greater than 200 .mu.g/cm.sup.2.h. Even Saran.RTM., frequently the material of choice in situations where maximum barrier properties are required, exhibits a permeability for nicotine of 8 .mu.g.100 .mu.m/cm.sup.2.h. From this exemplary discussion, it can be seen that designing a practical transdermal patch capable of both holding its nicotine load and dispensing it at an appropriate rate is a challenging problem. Some of the individual problems that must be resolved include:
1. Find a membrane or matrix material that is nicotine resistant or compatible. PA0 2. Find a membrane or matrix material that can give a safe, useful in vitro nicotine flux in the present context, i.e. neither excessively high nor low when compared to the skin flux. PA0 3. Find a nicotine-resistant adhesive with acceptable flux characteristics. PA0 4. Find materials for backings and peel strips that are nicotine resistant and nicotine-impermeable. PA0 5. Design a storage system that gives the patch a reasonable shelf-life.
Acceptable answers to these problems depend on the type of patch required. A non-controlled release patch, in other words one that occlusively covers a known area of skin, but permits uncontrolled exposure of that skin to nicotine, is less difficult to develop than one that meters the nicotine flux to the skin. The tape described in Japanese Laid Open Application No. 61-251619 is representative of this type of system. Such a patch cannot hold more than a low percentage loading of nicotine, and thus must cover a very large area of skin to be effective for even relatively short periods. In general, the smaller and more inconspicuous is a patch, the better is it accepted by patients. Therefore, patches that need to cover as much as 70 cm.sup.2 of skin, as described in the Japanese application, are not well received by patients.
A system that can hold and deliver sufficient nicotine to replace the plasma level obtained from smoking a single cigarette is also less difficult to develop than one that must regulate a nicotine load 20 or more times greater. U.S. Pat. No. 4,597,961 is representative of the single cigarette approach. The patches described therein are either non-controlled release embodiments designed to hold the nicotine load in occlusive contact with the skin, or controlled release embodiments where the nicotine flux is regulated to some extent by a microporous membrane. This approach is effective for short periods, but nicotine can pass through the microporous membrane with minimal resistance, so that the system cannot last longer than about 45 minutes.
Both these approaches are useful, although neither can exploit the real benefits of controlled release transdermal therapy. In general, one of the recognized advantages of transdermal therapy as opposed to other drug administration techniques is the simplicity of the dosage regime. A patient using a transdermal patch is less likely to encounter compliance problems than one who is required to swallow pills two or three times a day, subject himself to percutaneous infusion or injection, etc. Also a transdermal patch that has to be changed regularly once a day or once a week, for example, is preferred over one that has to be replaced several times a day, twice a week or on an irregular schedule. Another major advantage of continuous transdermal delivery is that the blood plasma levels of the delivered agent remain relatively steady. In this way, the periodic fluctuations between plasma levels above the safe threshold and below the efficacy threshold that are often seen with oral tablets or injections are eliminated, as are the "highs" associated with addictive substances.
The reasons that currently available transdermal nicotine systems are not prolonged-effect, controlled-release systems are twofold, and both relate to the properties of nicotine. First, as already discussed, nicotine's low melting point and activity make it a good candidate for transdermal administration because it is easy to get through the skin. Skin is a very impermeable membrane, with resistance characteristics equivalent to a silicone rubber layer 10 mm thick. Therefore, substances that can permeate the skin easily can permeate most synthetic polymer films even more easily. Consequently it is a matter of real difficulty, and to applicants' knowledge a previously unsolved problem, to find materials and components, and to make systems, that can hold sufficient nicotine for prolonged periods, and to release that nicotine in a safe, controlled fashion.
The second issue that hampers the development of prolonged-activity systems relates to the clinical properties of nicotine, specifically skin irritation and toxicity. Nicotine is a known skin irritant, and a patch that exposes the skin to raw nicotine for any length of time is unacceptable. More importantly, nicotine is a very toxic substance. The lethal unit dose for an average adult is about 60 mg; one cigarette delivers about 1 mg nicotine. Therefore a patch that is to be effective for 12 or 24 hours, for an average smoker, must contain a nicotine load that is 50% or more of the average lethal dose. A single patch may contain a lethal dose if tampered with or ingested by a child, for example. Thus safety is a major concern. In addition to the purely technological problems already discussed, then, a system that contains a high nicotine load must also be able to control release of that load in such a way that an individual using the patch on his skin is never exposed to a toxic dose. In addition, opportunities for accidental or deliberate misuse must be minimized if possible. Based on these considerations, it is clear that an effective, safe long-acting system must be more than a system of the types exemplified in U.S. Pat. No. 4,597,961 or Japanese Laid Open Application No. 61-251619, modified to hold a bigger nicotine load.
An additional clinical factor to be taken into account is the addictive nature of nicotine. The powerful morning craving for a cigarette experienced by smokers is a manifestation of the very low nicotine plasma level that occurs after 8 to 12 hours without smoking. A regime that can sustain through the night a nicotine plasma level that reduces or eliminates that craving would thus be a breakthrough in smoking cessation therapy. Chewing gums, oral administration, or short-term transdermal patches fail in this respect.
In summary, then, a preferred transdermal regime is one in which a low, steady dose of nicotine is maintained throughout the day and/or night by a single patch application. However, the type of patch that can provide such a regime is large quantity of nicotine, must retain that nicotine throughout its shelf life, and must release it in a safe and controlled manner when applied to the skin. Extensive discussion above is intended to make clear the particular difficulties that are encountered in the design and development of a transdermal nicotine patch, especially one that is effective for prolonged periods. Recognizing the advantages that could be offered by a hypothetical transdermal system is altogether a different matter than possessing the technology to enable a workable system to be made. And the knowledge of systems that are non-controlled release, or are effective for short periods, is altogether a different matter than possession of the technology to provide a useable system that can be effective for periods of up to a day or more. To the applicants' knowledge a transdermal nicotine delivery system that can sustain a safe, effective dose of nicotine for 12 hours or more is not yet available, nor has a description of such a system been published.